The neutral insulin solution introduced as Actrapid (registered trademark) nearly 40 years ago can be stored for several years at room temperature without significant change or loss of biological activity.
However, many investigators working with continuous insulin infusion from delivery device have noted the progressive propensity of insulin in solution to aggregate and form precipitate. Therefore, this inherent tendency of insulin to form aggregate or fibrils by non-covalent polymerization, which is promoted by a combination of physical factors, such as heat, movement, and hydrophobic surfaces, presents a major impediment to safe clinical application of insulin drug delivery systems.
Many different ways of increasing the physical stability of insulin for use in infusion pump have been reported. These methods include the use of organic medium, the introduction of organic and inorganic additives, and the use of insulin derivates.
Only a few of these methods are effective without compromising the quality of insulin preparation. For example the addition of two extra Zn2+ per hexamer of insulin has demonstrated an improved physical stability without affecting the chemical stability of the corresponding insulin solution.
Insulin fibril formation involves the dissociation of native associated states (hexamer, tetramer, and dimer) to give native monomer. Therefore, by stabilizing the hexamer insulin with two extra Zn2+, the formation of the intermediate which then oligomerizes to form transient soluble oligomers that lead to a fibril nucleus will be strongly reduced resulting in an improved stability, i.e. a longer fibrillation lag time.
However, it has been reported that the addition of 0.5% fibril seeds to a fresh insulin solution results in a 10-fold decrease in the lag time and addition of fibril seeds at concentrations of 1, 5, and 10% relative to the concentration of the native insulin completely eliminated the lag phase.
These results demonstrate the dramatic effect of seeding on the lag time which is directly related to the length of time it takes to form the fibril nucleation.
The methods which have been disclosed so far, to improve physical stability of insulin solution in infusion system, have been focused on the preparation of new insulin formulations improving the physical stability of the insulin when exposed to high mechanical stress or high temperature.
They more particularly aim at improving delivery of insulin with continuous infusion devices which comprise a reservoir filled with the drug to be delivered to a patient and connected to the patient's body. Such devices are usually attached to the patient's body to be operative several days, while the reservoir may eventually be refilled periodically. Thus, the patient's body heat and the patient's motions create flow movements in the reservoir as well as in the tubing and pump of the device imparting a high amount of thermo-mechanical energy to the drug solution.
Prior art proposals to improve physical stability of insulin solutions are discussed in patent EP 1 283 051 B1, in which further stable insulin formulations are disclosed. However, such stabilized formulations do not completely address the potential risk of limited compatibility of the tubing and of the pump material with the insulin for long duration exposition, more especially when the infusion device has small dimensions, i.e. when it is a micro-device.
Indeed, a continuous exposure to condition simulating insulin infusion, in particular, is expected to accelerate the fibrillation process.
In a drug infusion system, the solution may reside in the reservoir for several days, which will promote fibril seeds formation, even with the above-mentioned stabilized formulations. If the amount of these fibrils is not an issue in term of insulin stability, the presence of these seeds represents a real problem for the functionality of the infusion system when the solution enters downstream of the fluidic path.
In fact, seeding a solution with preformed insulin aggregates markedly accelerates the rate of aggregate, which can alter some functionality of the device downstream of the reservoir such as the leaktightness of the system or the fluidic resistance of a channel or also modify the efficacy of the insulin itself.
This is particularly relevant if the fibrillation mechanism is promoted downstream of the reservoir by environmental conditions such as reservoir material, gas bubbles, temperature or shear forces. Therefore, the prevention of fibrillation in a device remains an important challenge to address.